Reactivation of latent HIV: do all roads go through P-TEFb?

The HIV/AIDS field is gaining momentum in the goal of finding a functional cure for HIV infection by utilizing strategies that specifically reactivate the latent viral reservoir in combination with the HAART regimen to prevent further viral spread. Small-molecule inhibitors such as histone deacetylase (HDAC) and bromodomain and extraterminal (BET) inhibitors can successfully activate HIV transcription and reverse viral latency in clonal cell lines. However, in resting CD4(+) T cells, thought to be the principal physiological reservoir of latent HIV, their effect in reactivating the viral reservoir is more variable. It is possible that the discrepant responsiveness of quiescent primary CD4(+) T cells to HDAC and BET inhibitors could be attributed to the limiting levels of P-TEFb, a key viral transcription host cofactor, in these cells. In this review, we discuss the role of P-TEFb and the necessity for its mobilization in stimulating viral reactivation from latency upon treatment with HDAC and BET inhibitors.